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dc.contributor.authorPakdaman, Yasamanen_US
dc.contributor.authorSanchez Guixe, Monicaen_US
dc.contributor.authorKleppe, Runeen_US
dc.contributor.authorErdal, Sigriden_US
dc.contributor.authorBustad, Helene J.en_US
dc.contributor.authorBjørkhaug, Liseen_US
dc.contributor.authorHaugarvoll, Kristofferen_US
dc.contributor.authorTzoulis, Charalamposen_US
dc.contributor.authorHeimdal, Ketil Riddervolden_US
dc.contributor.authorKnappskog, Peren_US
dc.contributor.authorJohansson, Stefanen_US
dc.contributor.authorAukrust, Ingvilden_US
dc.PublishedPakdaman Y, Sanchez Guixe M, Kleppe R, Erdal S, Bustad HJ, Bjørkhaug L, Haugarvoll K, Tzoulis C, Heimdal Kr, Knappskog PM, Johansson S, Aukrust I. In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins. Bioscience Reports. 2017;37(2):BSR20170251eng
dc.description.abstractSpinocerebellar ataxia, autosomal recessive 16 (SCAR16) is caused by biallelic mutations in the STIP1 homology and U-box containing protein 1 (STUB1) gene encoding the ubiquitin E3 ligase and dimeric co-chaperone C-terminus of Hsc70-interacting protein (CHIP). It has been proposed that the disease mechanism is related to CHIP’s impaired E3 ubiquitin ligase properties and/or interaction with its chaperones. However, there is limited knowledge on how these mutations affect the stability, folding, and protein structure of CHIP itself. To gain further insight, six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M) were expressed as recombinant proteins and studied using limited proteolysis, size-exclusion chromatography (SEC), and circular dichroism (CD). Our results reveal that N65S shows increased CHIP dimerization, higher levels of α-helical content, and decreased degradation rate compared with wild-type (WT) CHIP. By contrast, T246M demonstrates a strong tendency for aggregation, a more flexible protein structure, decreased levels of α-helical structures, and increased degradation rate compared with WT CHIP. E28K, K145Q, M211I, and S236T also show defects on structural properties compared with WT CHIP, although less profound than what observed for N65S and T246M. In conclusion, our results illustrate that some STUB1 mutations known to cause recessive SCAR16 have a profound impact on the protein structure, stability, and ability of CHIP to dimerize in vitro. These results add to the growing understanding on the mechanisms behind the disorder.en_US
dc.publisherPortland Presseng
dc.rightsAttribution CC BYeng
dc.titleIn vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteinsen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2017 The Authors
dc.source.journalBioscience Reports
dc.relation.projectNorges forskningsråd: 240369
dc.identifier.citationBioscience Reports. 2017, 37 (2), BSR20170251.

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